EP0541550B1 - Intermédiaires nouveaux, leur préparation et utilisation - Google Patents

Intermédiaires nouveaux, leur préparation et utilisation Download PDF

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Publication number
EP0541550B1
EP0541550B1 EP90917427A EP90917427A EP0541550B1 EP 0541550 B1 EP0541550 B1 EP 0541550B1 EP 90917427 A EP90917427 A EP 90917427A EP 90917427 A EP90917427 A EP 90917427A EP 0541550 B1 EP0541550 B1 EP 0541550B1
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EP
European Patent Office
Prior art keywords
formula
carbonochloridate
hydrogen
mmol
stands
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP90917427A
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German (de)
English (en)
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EP0541550A1 (fr
Inventor
Frantz Johannes Lund
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Leo Pharma AS
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Leo Pharmaceutical Products Ltd AS
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C329/00—Thiocarbonic acids; Halides, esters or anhydrides thereof
    • C07C329/02—Monothiocarbonic acids; Derivatives thereof
    • C07C329/04—Esters of monothiocarbonic acids
    • C07C329/06—Esters of monothiocarbonic acids having sulfur atoms of thiocarbonic groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to hitherto unknown intermediates of the below formula I for use in the synthesis of prodrugs.
  • the said prodrug is non-toxic and, when administered to a warm-blooded animal including a human being, is enzymatically and/or chemically cleaved in such a manner as to release the drug at its target or site of activity, quantitatively and at a desirable rate, while the remaining cleaved moiety remains non-toxic and is metabolized in such a manner that non-toxic metabolic products are produced.
  • the prodrug can be provided without excessive costs in connection with its production, in particular without an appreciable loss of drug itself during its production and recovery, since the drug is usually the more expensive part of the prodrug.
  • the intermediate used to react with the drug in providing the prodrug should advantageously be stable and still be reasonably reactive.
  • acyloxyalkoxycarbonyl derivatives have become interesting bioreversible prodrug moieties of drugs and medicaments which are more readily bioavailable than the drug itself, and further are less irritating to topical and gastric mucosal membranes and are more permeable through such membranes.
  • R 1 may be further substituted, and its chain be interrupted by hetero atoms like oxygen, or by carbonyl group(s).
  • R 3 means hydrogen or C 1 -C 3 alkyl. Esters of this type have for instance been used as prodrugs of R'COOH and have been shown to be enzymatically hydrolyzed in man. Obviously such esters will also liberate D-H.
  • esters of the formula II have been produced in a multi-step procedure, confer J. Med. Chem. 1988, 31, p. 318ff, where the drug (containing a primary or secondary amine group being the point of reaction) is reacted with a compound of formula III in which formula, R 1' and R are hydrogen or lower alkyl.
  • the relationship between the reactivities of the two electrophilic centres in (3) is temporarily reversed by conversion of the acid chloride function to the less reactive carbonothioate group of (4).
  • the acid chloride function of (7) (being the desired intermediate of formula I) is finally restored by chlorination.
  • the double esters (6) were mostly prepared by stirring a suspension of sodium carboxylate in dimethylformamide with the iodo compound (5) at room temperature for 20 hours.
  • Simple carboxylic acids tend to give higher yields (80-100%) than carboxylic acids containing additional functional groups.
  • Other methods are workable, confer e.g. Scheme A, methods E, F, and J (Examples 9, 10, and 14, respectively).
  • the double esters (6) were generally pure enough for subsequent conversion, in step 4 of Scheme A, to the desired intermediates (7) by restoring the acid chloride function through reaction with sulfuryl chloride, preferably in the presence of a catalytic amount of boron trifluoride etherate at -25 - -30 ° C and subsequent stirring at 0 ° C for one hour and half an hour at room temperature.
  • the distillable compounds (7) were produced in high yields and could be kept without deterioration for years in a refrigerator.
  • the synthetic sequence is not restricted to acyloxymethyl carbonochloridates.
  • 1-chloroalkyl carbonochloridates for (3) and treating the derived 0-1-chloroalkyl S-alkyl carbonothioate with TBA butanoate in tetrahydrofuran for a suitable period of time, followed by sulfuryl chloride treatment provided a solution of 1-butanoyloxyalkyl carbonochloridate, but these intermediates seem to be less stable than (7).
  • the present intermediates of formula I can generally be prepared by reacting a 1-haloalkyl carbonochloridate of the formula IV where R 3 has the above meanings, is reacted with R 2 SR 4 , R 2 being C 1 -C 4 alkyl, and R 4 being hydrogen or an alkali metal ion, to form a 1-haloalkyl carbonothioate of the formula V R 2 and R 3 having the above meanings, which is transformed into a 1-acyloxyalkyl carbonothioate of the formula VI R 1 , R 2 , and R 3 having the above meanings, by reaction with a salt of a carboxylic acid R 1 COOH, R 1 having the above meanings, and finally reacting the compound of formula VI with a chlorinating agent to yield the desired intermediate of formula I.
  • R 3 H
  • the present intermediates are preferably being prepared by converting the compound of formula V to the corresponding iodide by reaction with sodium iodide, before transforming it via VI to I.
  • the preferred chlorinating agent used in the final step of the preparation of the present intermediates is sulfuryl chloride.
  • the present intermediates of the formula I can be provided in good yields and of reasonable costs, that they are stable, and even very reactive, in their intended use in the production of prodrugs. Due to the polyfunctionality of the intermediates, and the known catalytic decomposition of simple alkyl carbonochloridates, acylation reactions like the one used in providing the desired prodrugs could be expected to be troublesome, but this turned out not to be so, as illustrated by the non-optimized reactions of I with a few hydroxyl or amino group containing compounds (Examples 16-21).
  • the present intermediates are effective means in the production of the prodrugs in question, and they provide said final prodrugs in good yields in one step processes.
  • Example 3 The Procedure of Example 3 is slightly modified by increasing the amount of Nal to 30 g (200 ml), adding NaHCO 3 (0.8 g, 10 mmol), and heating at 40 °C for 4 h. Yield: 23.1 g (94%).

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Furan Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Claims (8)

1. Un produit intermédiaire pour la préparation des prodrugs (promédicaments), l'intermédiaire ayant la formule I
Figure imgb0058
dans laquelle R1 désigne un atome d'hydrogène ou une chaîne carbonée en C1-C20 aliphatique linéaire ou ramifiée ou un groupe aryle ou aralkyle, aryle et "ar" désignant un substituant cyclique à 5- ou 6- chaînons aromatique ou hétérocyclique contenant 1 ou 2 hétéroatomes choisis parmi O, S et N ; R1 étant éventuellement substitué, et sa chaîne éventuellement étant interrompue par des hétéroatomes tels que l'oxygène ou par des groupes carbonyles ; et R3 désignant l'atome d'hydrogène ou un groupe C1-C3 alkyle.
2. Un produit intermédiaire de formule 1 selon la revendication 1, selon laquelle R3 désigne un atome d'hydrogène.
3. Un produit intermédiaire de formule 1 selon la revendication 1, selon laquelle R1 désigne un substituant aromatique ou hétérocyclique choisi dans le groupe comprenant les suivants : phényle, furyle, thiényle, pyrrolyle, imidazolyle, thiazolyle, oxazolyle, pyridyle et pyrimidinyle.
4. Un produit intermédiaire selon la revendication 1 choisi dans le groupe comprenant les suivants :
a) carbonochloridate d'acétyloxyméthyle
b) carbonochloridate de propanoyloxyméthyle
c) carbonochloridate de butanoyloxyméthyle
d) carbonochloridate de pentanoyloxyméthyle
e) carbonochloridate de benzoyloxyméthyle
5. Procédé de production d'un produit intermédiaire de formule 1 selon la revendication 1, selon laquelle un dérivé de carbonochloridate de 1-haloalkyle de formule IV
Figure imgb0059
dans laquelle R3 qui est défini comme ci-dessus est mins à réagir avec le R2SR4, R2 étant un groupe C1-C4 alkyle, et R4 étant un atome d'hydrogène ou un ion de métal alcalin, pour former un carbonothioate de 1-haloalkyle de formule V
Figure imgb0060
R2 et R3 ayant les définitions données précédemment, qui est transformé en un carbonothioate de 1- acyloxyalkyle de formule VI
Figure imgb0061
 R1, R2 et R3 ayant les significations précédentes, par réaction avec un sel d'un acide carboxylique R1COOH, R1 ayant la signification précédente, et réaction finale du composé de formule VI avec un agent de chloruration pour donner le produit intermédiaire désiré de formule I.
6. Un procédé selon la revendication 5, selon laquelle un produit intermédiaire de formule I de la revendication 1 (R3 = hydrogène) est préparé par conversion du composé de formule V en un iodure correspondant par réaction avec l'iodure de sodium, avant sa transformation via VI en I.
7. Un procédé selon la revendication 5 ou 6, selon laquelle l'agent de chloruration est le chlorure de sulfuryle.
8. Utilisation d'un produit intermédiaire de formule I de la revendication 1 dans la production d'un prodrug de formula Il
Figure imgb0062
dans laquelle R1 et R3 sont comme décrit précédemment, et D-H = le médicament, D-H contenant un groupe OH, SH, NH2 ou une fonction N monosubstituée.
EP90917427A 1990-01-22 1990-11-28 Intermédiaires nouveaux, leur préparation et utilisation Expired - Lifetime EP0541550B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9001405 1990-01-22
GB909001405A GB9001405D0 (en) 1990-01-22 1990-01-22 New intermediates,their production and use
PCT/DK1990/000308 WO1991010639A1 (fr) 1990-01-22 1990-11-28 Nouveaux intermediaires, production et utilisation

Publications (2)

Publication Number Publication Date
EP0541550A1 EP0541550A1 (fr) 1993-05-19
EP0541550B1 true EP0541550B1 (fr) 1994-09-07

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EP90917427A Expired - Lifetime EP0541550B1 (fr) 1990-01-22 1990-11-28 Intermédiaires nouveaux, leur préparation et utilisation

Country Status (13)

Country Link
US (1) US5401868A (fr)
EP (1) EP0541550B1 (fr)
JP (1) JP3025532B2 (fr)
AT (1) ATE111073T1 (fr)
AU (1) AU6883191A (fr)
CA (1) CA2064872C (fr)
DE (1) DE69012351T2 (fr)
DK (1) DK0541550T3 (fr)
ES (1) ES2061077T3 (fr)
GB (1) GB9001405D0 (fr)
HU (1) HUT60459A (fr)
IE (1) IE64470B1 (fr)
WO (1) WO1991010639A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7790708B2 (en) 2001-06-11 2010-09-07 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof

Families Citing this family (20)

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Publication number Priority date Publication date Assignee Title
WO2001005768A1 (fr) 1999-07-19 2001-01-25 Shionogi & Co., Ltd. Composes tricycliques porteurs de pendants acyloxymethoxycarbonyle
US6376548B1 (en) 2000-01-28 2002-04-23 Rohm And Haas Company Enhanced propertied pesticides
WO2001054481A2 (fr) * 2000-01-28 2001-08-02 Rohm And Haas Company Produits pharmaceutiques aux proprietes ameliorees
US7232924B2 (en) * 2001-06-11 2007-06-19 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
IL159299A0 (en) * 2001-06-11 2004-06-01 Xenoport Inc Orally administered dosage forms of gaba analog prodrugs having reduced toxicity
US6818787B2 (en) * 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US6927036B2 (en) * 2002-02-19 2005-08-09 Xero Port, Inc. Methods for synthesis of prodrugs from 1-acyl-alkyl derivatives and compositions thereof
PA8579701A1 (es) * 2002-08-23 2005-05-24 Pfizer Prod Inc Profarmaco inhibidor de beta-lactamasa
EP1636240A1 (fr) * 2003-06-05 2006-03-22 Pfizer Products Inc. Promedicament inhibiteur de la beta-lactamase
WO2005010011A2 (fr) * 2003-07-15 2005-02-03 Xenoport, Inc. Synthese de composes acyloxyalkyliques
AU2004267100B2 (en) 2003-08-20 2010-10-07 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
ES2405329T3 (es) 2003-12-30 2013-05-30 Xenoport, Inc. Síntesis de profármacos de carbarnato de aciloxialquilo y productos intermedios de los mismos
CN101486668B (zh) * 2003-12-30 2014-07-02 什诺波特有限公司 酰氧基烃基氨基甲酸酯前药及其中间体的合成
JP4938771B2 (ja) * 2005-06-20 2012-05-23 ゼノポート，インコーポレーテッド トラネキサム酸のカルバミン酸アシルオキシアルキルプロドラッグ、合成法、および使用
TW200820963A (en) * 2006-07-28 2008-05-16 Xenoport Inc Acyloxyalkyl carbamate prodrugs of α-amino acids, methods of synthesis and use
WO2010008886A2 (fr) * 2008-06-24 2010-01-21 Teva Pharmaceutical Industries Ltd. Procédés de préparation de promédicaments contenant de la gabapentine et de leurs intermédiaires
US20110060040A1 (en) * 2009-09-04 2011-03-10 Xenoport, Inc. Uses of acyloxyalkyl carbamate prodrugs of tranexamic acid
JP6105207B2 (ja) * 2012-03-30 2017-03-29 美津濃株式会社 ラケットフレーム
US20140024621A1 (en) 2012-07-23 2014-01-23 Ms Therapeutics Limited Aminopyridine compounds and their uses
JP7440939B2 (ja) * 2020-08-13 2024-02-29 南京海融医薬科技股▲フン▼有限公司 イブプロフェンエステル系プロドラッグ、医薬組成物、調製方法および使用

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7790708B2 (en) 2001-06-11 2010-09-07 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8168623B2 (en) 2001-06-11 2012-05-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8367722B2 (en) 2001-06-11 2013-02-05 Xenoport, Inc. Methods of using prodrugs of pregabalin
US9238616B2 (en) 2001-06-11 2016-01-19 Xenoport, Inc. Prodrugs of gaba analogs, compositions and uses thereof
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof

Also Published As

Publication number Publication date
AU6883191A (en) 1991-08-05
JPH05503925A (ja) 1993-06-24
WO1991010639A1 (fr) 1991-07-25
IE904309A1 (en) 1991-07-31
JP3025532B2 (ja) 2000-03-27
DK0541550T3 (da) 1994-10-17
US5401868A (en) 1995-03-28
GB9001405D0 (en) 1990-03-21
CA2064872A1 (fr) 1991-07-23
EP0541550A1 (fr) 1993-05-19
DE69012351T2 (de) 1995-02-09
CA2064872C (fr) 2002-01-22
HUT60459A (en) 1992-09-28
ATE111073T1 (de) 1994-09-15
ES2061077T3 (es) 1994-12-01
DE69012351D1 (de) 1994-10-13
IE64470B1 (en) 1995-08-09
HU9200477D0 (en) 1992-08-28

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